III. Four important areas related to natural history or management of patients with gastrinomas and other pancreatic endocrine tumors (PET's) were examined during this time period. III.A. Role of somatostatin receptor scintigraphy (SRS) in patients with gastrinomas. III.A.1. Prospective study of the ability of SRS, bone scan and MRI to identify bone metastases in patients with gastrinomas. The frequency of bone metastases, the best method of detection and their effect on clinical management in patients with PET's is largely unknown. To address these issues a prospective study of 115 patients with gastrinomas was performed using bone scan, SRS and MRI to identify bone metastases. Bone metastases are present in 31% of patients with liver metastases which is much higher number than previously reported. SRS had the highest sensitivity and specificity for their detection. Their detection affected management in all cases. III.A.2. Ability of SRS and other imaging studies to differentiate liver metastases from hepatic hemangiomas. A prospective study involved 28 patients with hepatic hypervascular lesions demonstrated SRS was superior to existing imaging techniques and is now the imaging procedure of choice for this differentiation. III.B. Management of Zollinger-Ellison syndrome (ZES in pregnancy. The management of this syndrome in pregnancy has not been studied. Five patients having 7 pregnancies were managed successfully using different strategies to control acid hypersecretion and the gastrinoma. Based on these cases an overall approach to managing patients with ZES during pregnancy was proposed. III.C. Natural history of untreated metastatic liver disease in patients with ZES. The growth pattern of liver metastases without treatments of any malignant PET is largely unknown and yet, an understanding of this is pertinent to decide when to recommend various anti-tumor therapies. This was prospectively studied in 19 patients with metastatic gastrinoma. In 26% of patients no tumor growth occurred in a 2.5 year period, 32% had slow growth, and 42% rapid growth. Various clinical and laboratory parameters were examined for their predictive value and the effects of this variable growth on currently recommended antitumor strategies was examined. III.D. Gene defects in gastrinomas or gastric carcinoid tumors of patients with MEN-1 and gastrinomas of patients with sporadic ZES. Both studies were performed in collaboration primarily with I. Lubensky (NCI, Pathology). In one study 44% of sporadic gastrinomas, and 41% of MEN-1 gastrinomas had loss of heterozygosity at the 11q13/locus, which is now known to be the location of the MEN-1 gene. In a second study, 75% of gastric carcinoids in patients with MEN-1 but only 16% in patients without MEN-1 had a loss of heterozygosity at this locus demonstrating gastric carcinoids are an independent tumor type due to the MEN-1 defect and not a secondary event.